This theory suggests that the virus or its components may remain in the body long after the initial infection and even after a person tests negative. The virus may hide in the cells and reactivate under certain conditions. Additionally, there could be viral RNA and proteins that linger even after the virus has left the body, resulting in an activated immune response. The immune system, unable to rid the virus in certain organs of the body, remains in an inflamed state.¹⁶

This theory involves a chain reaction of cellular physiology. Evidence suggests that COVID-19 can cause abnormal triggering of mast cells, the first line of immune defense. For those with MCAS, this causes the immune system to act erratically and makes the person even sicker.¹³ This process can also be linked to depletion of NAD+,¹² a coenzyme that helps metabolic enzymes work efficiently. Depletion of NAD+ can further impair cellular processes and mast cell function.

This theory proposes failure of the immune system to reset after the overactive stage of the initial infection.⁸ Along with systemic inflammation, COVID-19 can create an ongoing autoimmune response that attacks the body.⁹

This theory hypothesizes that long-haulers are experiencing a combination of multiple illnesses: permanent organ damage to the lungs and heart, post-intensive care syndrome, post-viral fatigue syndrome, and continuing COVID-19 symptoms.¹¹ While one person may suffer from one or two of the associated illnesses, others may be struggling with even more. This would explain why the symptoms and severity of PASC vary so greatly from person to person.

This theory proposes that COVID-19 hijacks the mitochondria (the cell’s batteries) of the immune cells and impairs mitochondrial pathways. This manipulates the functions of the cells for the advantage of COVID-19 viral replication. The virus drains the mitochondria’s power, leaving little left for the cell to use for itself.

This hypothesis focuses on the fact that the brainstem is highly prone to damage from immune activation, which is common in COVID-19 cases. The brainstem contains nuclei that regulate the respiratory, cardiovascular, gastrointestinal, and neurological processes, imbalance of which can be linked to PASC, and can overlap with COVID-19 symptoms¹⁴

Dormant pathogens in the body prior to a COVID-19 infection can reappear and exacerbate symptoms. These can include bacteria, parasites, fungal organisms, and viruses. Many pathogens can linger in the body, but under normal conditions are controlled by a healthy immune system. When infected by COVID-19, the immune system is overwhelmed, leaving room for dormant pathogens to reactivate and cause symptoms.¹⁷

This theory explains that COVID-19 may deplete important microorganisms in the gut microbiome, potentially contributing to PASC symptoms.¹⁸

This theory shows that an overload of various inflammatory molecules, literally "trapped" inside insoluble microscopic blood clots (micro clots), might be the cause of some of the lingering symptoms experienced by individuals with Long COVID (1).
Many long haulers continue to have higher measures of blood clotting markers, which might explain persisting symptoms such as fatigue and post-exertional malaise, even though their inflammatory markers may have returned to normal.